Humalog

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SIDE EFFECTS

Clinical Trial Experience

Because clinical trials are conducted under widely
varying designs, the adverse reaction rates reported in one clinical trial may
not be easily compared with those rates reported in another clinical trial, and
may not reflect the rates actually observed in clinical practice.

The frequencies of Treatment-Emergent Adverse Events
during HUMALOG clinical trials in patients with type 1 diabetes mellitus and
type 2 diabetes mellitus are listed in the tables below.

Insulin initiation and
intensification of glucose control

Intensification or rapid
improvement in glucose control has been associated with a transitory,
reversible ophthalmologic refraction disorder, worsening of diabetic
retinopathy, and acute painful peripheral neuropathy. However, long-term
glycemic control decreases the risk of diabetic retinopathy and neuropathy.

Lipodystrophy

Long-term use of insulin,
including HUMALOG, can cause lipodystrophy at the site of repeated insulin
injections or infusion. Lipodystrophy includes lipohypertrophy (thickening of
adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect
insulin absorption. Rotate insulin injection or infusion sites within the same
region to reduce the risk of lipodystrophy [see DOSAGE AND ADMINISTRATION].

Weight gain

Weight gain can occur with
insulin therapy, including HUMALOG, and has been attributed to the anabolic
effects of insulin and the decrease in glucosuria.

Peripheral Edema

Insulin, including HUMALOG, may
cause sodium retention and edema, particularly if previously poor metabolic
control is improved by intensified insulin therapy.

In a 12-week, randomized,
crossover study in adult patients with type 1 diabetes (n=39), the rates of
catheter occlusions and infusion site reactions were similar for HUMALOG and
regular human insulin treated patients (see Table 3).

Table 3: Catheter Occlusions and Infusion Site
Reactions

HUMALOG
(n=38)

Regular human insulin
(n=39)

Catheter occlusions/month

0.09

0.1

Infusion site reactions

2.6% (1/38)

2.6% (1/39)

In a randomized, 16-week,
open-label, parallel design study of children and adolescents with type 1
diabetes, adverse event reports related to infusion-site reactions were similar
for insulin lispro and insulin aspart (21% of 100 patients versus 17% of 198
patients, respectively). In both groups, the most frequently reported infusion
site adverse events were infusion site erythema and infusion site reaction.

Allergic Reactions

Local Allergy — As with any insulin
therapy, patients taking HUMALOG may experience redness, swelling, or itching
at the site of the injection. These minor reactions usually resolve in a few
days to a few weeks, but in some occasions, may require discontinuation of
HUMALOG. In some instances, these reactions may be related to factors other
than insulin, such as irritants in a skin cleansing agent or poor injection
technique.

Localized reactions and generalized myalgias have been
reported with injected metacresol, which is an excipient in HUMALOG [see CONTRAINDICATIONS].

Antibody Production

In large clinical trials with
patients with type 1 (n=509) and type 2 (n=262) diabetes mellitus, anti-insulin
antibody (insulin lispro-specific antibodies, insulin-specific antibodies,
cross-reactive antibodies) formation was evaluated in patients receiving both
regular human insulin and HUMALOG (including patients previously treated with
human insulin and naive patients). As expected, the largest increase in the
antibody levels occurred in patients new to insulin therapy. The antibody
levels peaked by 12 months and declined over the remaining years of the study.
These antibodies do not appear to cause deterioration in glycemic control or
necessitate an increase in insulin dose. There was no statistically significant
relationship between the change in the total daily insulin dose and the change
in percent antibody binding for any of the antibody types.

Postmarketing Experience

The following additional adverse reactions have been
identified during post-approval use of HUMALOG. Because these reactions are
reported voluntarily from a population of uncertain size, it is not always
possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.

Medication errors in which
other insulins have been accidentally substituted for HUMALOG have been
identified during postapproval use [see PATIENT INFORMATION].

Drugs That May Increase or Reduce the
Blood-Glucose-Lowering Effect of HUMALOG: beta-blockers, clonidine, lithium
salts, and alcohol. Pentamidine may cause hypoglycemia, which may sometimes be
followed by hyperglycemia.

Drugs That May Reduce the Signs of Hypoglycemia: beta-blockers,
clonidine, guanethidine, and reserpine.